Life Sciences Research for Lifelong Health

Establishing epigenetic marks in gametes: imprinting and beyond

Imprinted genes, which acquire different epigenetic marks in the egg and the sperm, have provided a paradigm for understanding the epigenetic patterning of the germlines. A classical component of this patterning is DNA methylation at imprinting control regions, but the factors that govern which parts of the genome become methylated in gametes are poorly understood.
 
We recently uncovered an essential role for gene transcription in establishment of DNA methylation marks at imprinted genes (Chotalia et al. 2009). When we survey the entire oocyte genome, we find that DNA methylation is located predominantly over active genes, indicating a general role for transcription events in instructing the DNA methylation profile of the egg (Veselovska et al. 2015).
 
We believe that transcription helps to remodel histone modifications in chromatin to a state that recruits the de novo DNA methylation complex. We are testing this model using a combination of genetic and highly sensitive molecular approaches, such as mapping histone modifications in oocytes and profiling DNA methylation changes in oocytes lacking candidate histone modifiers (Nashun et al. 2015).
 
The discovery that gene transcription is essential for DNA methylation and imprint establishment may help to explain how the methylome of the egg may be modified by adverse environments or how imprinting is disrupted in some imprinted gene disorders.
 
Stepwise modification of chromatin
Stepwise modification of chromatin in oocytes to enable DNA methylation establishment.
 
De novo DNA methylation is predicted to occur in regions of the genome marked by the modified histone H3K36me3 but devoid in histone H3K4 methylation. During oocyte growth and development, stepwise modification of chromatin brought about by factors such as H3K36 methyltransferases and H3K4 demethylases are part of the mechanism that generates a chromatin state permissive for DNA methylation.